Efavirenz is a substrate and in turn modulates the expression of the efflux transporter ABCG2/BCRP in the gastrointestinal tract of the rat Roxana N. Peroni a,b,c, *, Stefania S. Di Gennaro a , Christian Hocht b , Diego A. Chiappetta c,d , Modesto C. Rubio a,b,c , Alejandro Sosnik c,d , Guillermo F. Bramuglia b a Pharmacological Research Institute, National Science Research Council (CONICET), Argentina b Department of Pharmacology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina c National Science Research Council (CONICET), Argentina d The Group of Biomaterials and Nanotechnology for Improved Medicines (BIONIMED), Department of Pharmaceutical Technology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina 1. Introduction There are 15 million people living with the human immunode- ficiency virus (HIV) in low- and middle-income countries [44]. Efavirenz (EFV) is a first-line antiretroviral (ARV) included in the highly active antiretroviral therapy (HAART) that is prescribed to adults and children infected with HIV [1–3]. Its key role as an affordable treatment in developing countries is due to its relatively low cost, manageable pill burden, low viral resistance and well- documented efficacy and safety [4]. EFV is a highly lipophilic non-nucleoside reverse transcriptase inhibitor classified in class II of the Biopharmaceutic Classification System [5]. Its oral bioavailability is about 40–45% and it demands therapeutic drug monitoring (TDM) due to the inter- and intra- individual variability [6,7]. Some studies have highlighted the possible correlation between (a) low EFV plasma exposure and increased risk of therapeutic failure [8–10], and (b) high systemic exposure with toxicity, mainly in the central nervous system [10,11]. At least two factors are known to influence the pharmacoki- netics of EFV. First, the very low solubility of EFV in aqueous medium (<4 mg/ml) hinders the absorption and distribution of the drug from the gastrointestinal tract [12,13]. In general, a good correlation has been established between solubility improvement and higher bioavailability for most of the class II drugs [14,15]. In this sense, previous investigations showed that the encapsulation of EFV within polymeric micelles of different poly(ethylene oxide)–poly(propylene oxide) block copolymers [16] significantly improves the oral bioavailability of the drug and reduces the inter- individual variability [17,18]. Second, the hepatic activity of the cytochrome P450 2B6 (CYP2B6) that is the main metabolic route of EFV, can be modified. The inter-individual variability in the CYP2B6 function arises from Biochemical Pharmacology 82 (2011) 1227–1233 A R T I C L E I N F O Article history: Received 1 June 2011 Accepted 12 July 2011 Available online 23 July 2011 Keywords: Abcg2 Efavirenz Hiv Oral bioavailability Intestine A B S T R A C T The oral bioavailability of the antiretroviral efavirenz (EFV) undergoes high inter and intra-individual variability, this fact supporting its therapeutic drug monitoring. Previously, it was demonstrated that the encapsulation of EFV within polymeric micelles increases the oral bioavailability of the drug. The breast cancer resistant protein (BCRP, ABCG2) is known to be inhibited by EFV in vitro. Since ABCG2 is profusely expressed in the gastrointestinal tract, the aim of the present work was to thoroughly investigate whether the intestinal permeability of EFV is modulated by ABCG2. The functional role of ABCG2 in mediating the transport of EFV at the intestinal level was consistent with the following findings: (a) an ABCG2 inhibitor, fumitremorgin C (5–10 mM), significantly potentiated the mucosal-to-serosal permeation of the drug in everted gut sacs; (b) a five-day oral treatment with 20 mg/kg EFV promotes the over-expression of ABCG2 in about 100%, this phenomenon being accompanied by a clear decline in the intestinal permeability of the antiretroviral and (c) the normalization of the ABCG2 expression within 24 h after the last administration of EFV was coincident with the recovery of the ability of the drug to permeate through the small intestine wall. Interestingly, no interactions between EFV and P-glycoprotein (ABCB1) were apparent. Since the intestinal permeability of a drug could be associated with its in vivo absorbability, we suggest that the oral absorption of EFV is affected by modifications in the ABCG2 intestinal expression contributing to the intra-individual bioavailability variations. ß 2011 Elsevier Inc. All rights reserved. * Corresponding author at: Pharmacological Research Institute, National Science Research Council (CONICET), Argentina. Tel.: +54 11 49615949; fax: +54 11 49638593. E-mail address: rperoni@ffyb.uba.ar (R.N. Peroni). Contents lists available at ScienceDirect Biochemical Pharmacology jo u rn al h om epag e: ww w.els evier.c o m/lo cat e/bio c hem p har m 0006-2952/$ – see front matter ß 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.bcp.2011.07.081